The semisynthesis of morphine-derived antagonists, such as naloxone, nalbuphone, naltrexone and buprenorphine (see Scheme 1), and other medicinally significant compounds, from opium-derived natural products traditionally involves standard procedures for demethylation followed by subsequent procedures such as oxidation for the introduction of a C-14 hydroxyl group.

The challenge rests in the formal exchange of the N-methyl group of natural opiates for other functional groups, such as the N-cyclopropylmethyl, N-allyl, or N-cyclobutylmethyl functionality found in naltrexone, naloxone, nalbuphone and buprenorphine. The N-demethylation protocols previously reported include the von Braun reaction employing cyanogen bromide (Von Braun, J. Chem. Ber. 1980, 33, 1438), chloroformate reagents (Cooley, J. H.; Evain, E. J. Synthesis 1989, 1; Olofson, R. A. et al. J. Org. Chem. 1984, 49, 2081), photochemical methods (Ripper, J. A., et al. Biorg. & Med. Chem. Lett. 2001, 11, 443-445), demethylation of N-oxides [Polonovski reaction: (a) Kok, G. et al. Adv. Synth. Catal. 2009, 351, 283; (b) Dong, Z. et al. J. Org. Chem. 2007, 72, 9881; (c) Smith, C. et al. PCT Patent Application Publication No. WO 2005/028483], as well as microbial [(a) Madyashtha, K. M. et al. Proc. Indian Acad. Sci. 1984, 106, 1203; (b) Madyastha, K. M. et al. J. Chem. Soc. Perkin Trans. 1, 1994, 911] and enzymatic (Chaudhary, V. et al. Collect. Czech. Chem. Commun. 2009, 74, 1179) methods. The disadvantages of these methods are that the reagents are highly toxic (cyanogen bromide and ethylchloroformate) or proceed in poor yields (Polonovski and enzymatic methods) requiring significant purification of the desired secondary amine. The secondary amines are then converted to the corresponding products by alkylation.
Therefore any method that avoids these standard procedures may hold immense commercial potential for the production of morphine-derived alkaloids, such as naloxone, naltrexone, nalbuphone, buprenorphine and other medicinally significant compounds.
Current methods for N-demethylation of morphine alkaloids are time consuming, expensive and hazardous. Thus there was an unmet need for improvement in such methods. Furthermore, there is an increasing demand that production methods be environmentally friendly.